EP1967202A1 - Utilisation d'antagonistes LHTH pour le traitement des symptômes de tractus urinaires faibles, en particulier la vessie hyperactive et/ou hyperactivité du détrusor - Google Patents

Utilisation d'antagonistes LHTH pour le traitement des symptômes de tractus urinaires faibles, en particulier la vessie hyperactive et/ou hyperactivité du détrusor Download PDF

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Publication number
EP1967202A1
EP1967202A1 EP07103483A EP07103483A EP1967202A1 EP 1967202 A1 EP1967202 A1 EP 1967202A1 EP 07103483 A EP07103483 A EP 07103483A EP 07103483 A EP07103483 A EP 07103483A EP 1967202 A1 EP1967202 A1 EP 1967202A1
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EP
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Prior art keywords
treatment
month
overactive bladder
lhrh antagonist
lhrh
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EP07103483A
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German (de)
English (en)
Inventor
Jürgen Engel
Oliver Bauer
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Aeterna Zentaris GmbH
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Aeterna Zentaris GmbH
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Priority to EP07103483A priority Critical patent/EP1967202A1/fr
Priority to AU2008223841A priority patent/AU2008223841A1/en
Priority to BRPI0808488-2A priority patent/BRPI0808488A2/pt
Priority to PCT/EP2008/052640 priority patent/WO2008107446A1/fr
Priority to EP08709284A priority patent/EP2131854A1/fr
Priority to MX2009009320A priority patent/MX2009009320A/es
Priority to KR1020097018620A priority patent/KR20100014923A/ko
Priority to US12/042,522 priority patent/US20090075937A1/en
Priority to CN200880007201A priority patent/CN101657211A/zh
Priority to JP2009552194A priority patent/JP2010520257A/ja
Priority to CA002679690A priority patent/CA2679690A1/fr
Priority to RU2009136642/15A priority patent/RU2009136642A/ru
Publication of EP1967202A1 publication Critical patent/EP1967202A1/fr
Priority to ZA200905306A priority patent/ZA200905306B/xx
Priority to IL200182A priority patent/IL200182A0/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the use of LHRH antagonists for the treatment or prophylaxis of lower urinary tract symptom in mammals.
  • Such lower urinary tract symptom comprise urinary incontinence, urge incontinence, overactive bladder, idiopathic overactive bladder, neurogenic overactive bladder, detrusor overactivity, idiopathic detrusor overactivity, neurogenic detrusor overactivity and benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the invention further relates to the treatment or prophylaxis of above symptoms by administering LHRH antagonists in intermediate doses, which do not cause chemical (hormonal) castration.
  • Genitourinary problems including neurogenic dysfunction, such as incontinence and urinary retention, impotence, prostatism, urinary tract infections (UTI), benign prostatic hyperplasia/hypertrophy (BPH) and prostate cancer, are common in the elderly, and most of the symptoms can be alleviated through pharmacological management ( Atala A et al., Drugs & Aging 1991, 1(3): 176-193 ).
  • Overactive bladder is a syndrome characterized by urgency with or without urge incontinence, usually with increased frequency and nocturia.
  • Bladder overactivity can be myogenic or neurogenic in its origin or it can be idiopathic in nature.
  • Myogenic etiology is characterized by impairment in smooth muscle function as a result of partial urethral obstruction.
  • the increased smooth muscle signalling due to loss normal excitatory neural input leads to a state of unstable contractions or overactivity.
  • OAB is also triggered by neurological effects resulting in dysregulation of reflexes to the bladder and urethra and leading to neurogenic detrusor overactivity.
  • urinary incontinence is defined as an involuntary leakage accompanied by or immediately preceded by urgency ( Tiwari A et al., Expert Opin. Investig. Drugs 2006, 15(9): 1017-1037 ).
  • Atala et al. ( Atala A et al., Drugs & Aging 1991, 1(3): 176-193 ) mention the use of LHRH agonists, such as goserelin, leuprorelin, nafarelin and buserelin, to achieve castrate levels of androgens, for instance testosterone, in advanced prostatic carcinoma and BPH.
  • LHRH agonists such as goserelin, leuprorelin, nafarelin and buserelin
  • WO 02/36144 discloses the use of GnRH analogues for the treatment of side effects of ovarectomy or symptoms associated with reproductive senescence in female mammals, such as post-menopausal women and spayed bitches, in particular urinary incontinence, mood changes, hot flushes and skin/hair changes.
  • the patent application mentions GnRH agonists and antagonists, but is silent about the prevention of chemical (hormonal) castration and corresponding appropriate dosage schemes.
  • WO 02/36144 is only directed to female mammals and does not disclose the treatment of male human nor does it mention overactive bladder as medicinal indication.
  • GnRH antagonists used in discrete doses only: leuprolide acetate, deslorelin, triptorelin acetate, buserelin acetate in dose ranges from 3,75 mg to 12 mg.
  • GnRH agonists used in discrete doses only: leuprolide acetate, deslorelin, triptorelin acetate, buserelin acetate in dose ranges from 3,75 mg to 12 mg.
  • GnRH agonists in these doses inevitably leads to chemical (hormonal) castration and undesired unfavourable hormone withdrawal symptoms.
  • no experimental data are presented: the described experimental use of the GnRH agonist analogues is a mere hypothesis.
  • Reichler et al. describe the effect of GnRH analogues on urinary incontinence after ablation of the ovaries in dogs. Depot formulations of GnRH agonist analogues leuprolide, deslorelin, buserelin and triptorelin were used with dose ranges from 3,75 mg to 11,25 mg. Castration, i.e. reduction of gonadotrophins FSH and LH to basal or undetectable levels, is reported. The authors are silent about the use of LHRH antagonists, the prevention of chemical (hormonal) castration, corresponding appropriate dosage schemes and overactive bladder as medicinal indication ( Reichler IM et al., Theriogenology 2003, 60: 1207-1216 ).
  • Nitti reviews the status quo on botulinum toxin for the treatment of idiopathic and neurogenic overactive bladder and detrusor overactivity. The use of LHRH antagonists is not mentioned ( Nitti VW, Reviews in Urology 2006, 8(4): 198-208 ).
  • Kaplan et al. demonstrate efficacy of tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder in a randomized controlled trial ( Kaplan SA et al., JAMA 2006, 296(19): 2319-2328 ). The use of LHRH antagonists is not mentioned.
  • WO 2006/129162 is directed to anti-LHRH vaccines for the control or treatment of urinary incontinence.
  • the use of LHRH antagonists is not mentioned.
  • the present invention has the object to provide novel treatments for lower urinary tract symptoms, in particular overactive bladder and/or detrusor overactivity, by which negative hormone withdrawal symptoms are prevented.
  • the object of the invention has surprisingly been solved in one aspect by providing at least one LHRH antagonist that can be used for the preparation of a medicament for the treatment or prophylaxis of at least one lower urinary tract symptom in mammals, wherein the at least one lower urinary tract symptom is selected from the group consisting of: "urinary incontinence, urge incontinence, overactive bladder, idiopathic overactive bladder, neurogenic overactive bladder, detrusor overactivity, idiopathic detrusor overactivity, neurogenic detrusor overactivity" and wherein the at least one LHRH antagonist is to be administered in an intermediate dose, which does not cause chemical (hormonal) castration.
  • Overactive bladder is defined by the International Continence Society (ICS) as follows: Overactive bladder (OAB) is a symptom complex consisting of urgency with or without urge incontinence, usually with frequency and nocturia, in the absence of local pathologic or hormonal factors ( Abrams P et al., Urology 2003, 61(1): 37-49 ; Abrams P et al., Urology 2003, 62(Supplement 5B): 28-37 and 40-42 ). Synonyms of overactive bladder (OAB) include "urge syndrome” and "urge frequency syndrome”.
  • Detrusor overactivity is defined by the International Continence Society (ICS) as follows: Detrusor overactivity is a urodynamic observation characterized by involuntary detrusor contractions during the filling phase that may be spontaneous or provoked (Abrams P et al., Urology 2003, 62(Supplement 5B): 28-37 and 40-42).
  • intermediate dose in the course of the present invention is defined by its higher and lower limit and has the following meaning:
  • the higher limit of “intermediate dose” is the dose that just does not cause chemical (hormonal) castration as defined herein, wherein the lower limit of “intermediate dose” is the dose that just causes a lowering, even if a very small one, of LH, FSH and/or testosterone with regard to normal sex hormone blood levels. It lies within the knowledge of the skilled artisan to elaborate the lower and upper limit of an "intermediate dose” for each LHRH antagonist to be used on the basis of his expert knowledge and the disclosure of the present invention.
  • At least one LHRH antagonist is provided that can be used for the preparation of a medicament for the treatment or prophylaxis of at least one lower urinary tract symptom in mammals, wherein the at least one lower urinary tract symptom is selected from the group consisting of: "overactive bladder, idiopathic overactive bladder, neurogenic overactive bladder, detrusor overactivity, idiopathic detrusor overactivity, neurogenic detrusor overactivity" and wherein the at least one LHRH antagonist is to be administered in an intermediate dose, which does not cause chemical (hormonal) castration.
  • At least one LHRH antagonist is provided that can be used for the preparation of a medicament for the simultaneous treatment or prophylaxis of at least one lower urinary tract symptom selected from the group consisting of: "overactive bladder, idiopathic overactive bladder, neurogenic overactive bladder, detrusor overactivity, idiopathic detrusor overactivity, neurogenic detrusor overactivity” and benign prostatic hyperplasia (BPH), wherein the at least one LHRH antagonist is to be administered in an intermediate dose, which does not cause chemical (hormonal) castration.
  • BPH benign prostatic hyperplasia
  • patients can be treated that suffer from overactivce bladder and/or its subforms/etiologies idiopathic overactive bladder and/or neurogenic overactive bladder and benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • At least one LHRH antagonist is provided that can be used for the preparation of a medicament for the herein disclosed treatments, wherein the LHRH antagonist is selected from the group consisting of: "abarelix ( Chemical Abstract Services Registry Number: 183552-38-7 ), antide ( Chemical Abstract Services Registry Number: 112568-12-4 ), azaline B ( Chemical Abstract Services Registry Number: 134457-28-6), A-75998 ( Chemical Abstract Services Registry Number: 135215-95-1 ), cetrorelix ( Chemical Abstract Services Registry Number: 120287-85-6 ), degarelix ( Chemical Abstract Services Registry Number: 214766-78-6 ), detirelix ( Chemical Abstract Services Registry Number: 89662-30-6 ), ozarelix (D-63153) ( Chemical Abstract Services Registry Number: 295350-45-7 ), ganirelix ( Chemical Abstract Services Registry Number: 124904-93-4 ), Nal-Glu antagonist, ramorelix ( Chemical Abstract Services Registry Number: 127932-90-5), RS-68439 ( Chemical Abstract Services Registry
  • At least one LHRH antagonist as defined herein is provided that can be used for the preparation of a medicament for the herein disclosed treatments, wherein the intermediate dose is a total monthly dose in the range of 10 mg to 150 mg LHRH antagonist, preferably a total monthly dose in the range of 10 mg to 120 mg LHRH antagonist, more preferably a total monthly dose in the range of 10 mg to 40 mg LHRH antagonists, more preferably a total monthly dose in the range of 40 mg to 150 mg LHRH antagonists, more preferably a total monthly dose in the range of 60 mg to 150 mg LHRH antagonists, more preferably a total monthly dose in the range of 60 mg to 120 mg LHRH antagonists and most preferably a total monthly dose of 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 90 mg, 120 mg, 130 mg or 150 mg LHRH antagonist.
  • such total monthly dose is to be administered as one single monthly administration or is to be administered twice a month (preferably biweekly), three-times a month or four-times a month (preferably weekly).
  • a total monthly dose is to be administered biweekly or weekly, for instance, the total monthly dose is the sum of each single administration, where the single administrations need not to be identical. That is a total monthly dose of 40 mg LHRH antagonist can, for instance, be administered in two biweekly administrations of 20 mg + 20 mg or 30 mg + 10 mg or in four weekly administrations of 10 mg + 10 mg + 10 mg + 10 mg or 20 mg + 5 mg + 10 mg + 5 mg.
  • a total monthly dose of 90 mg LHRH antagonist can, for instance, be administered in two biweekly administrations of 60 mg + 30 mg or 30 mg + 60 mg or 45 mg + 45 mg or three-times a month as 30 mg + 30 mg + 30 mg.
  • At least one LHRH antagonist as defined herein is provided that can be used for the preparation of a medicament for the herein disclosed treatments with the herein disclosed doses, wherein the at least one LHRH antagonist is to be administered over a treatment period of 1 or 2 months followed by a treatment-free period of 1, 2, 3, 4 or 5 months, preferably 2 months or 5 months (one treatment cycle).
  • treatment cycle in the course of the present invention is defined as a treatment period of 1 or 2 months followed by a treatment-free period of at least one and up to five months. That is the shortest treatment cycle consists of a one-month treatment period and a one-month treatment-free period, whereas the longest treatment cycle consists of a two-months treatment period and a five-months treatment-free period. Preferred are a treatment cycle with a one-month or two-months treatment period and a two-months treatment-free period and a treatment cycle with a one-month or two-months treatment period and a five-months treatment-free period.
  • At least one LHRH antagonist as defined herein is provided that can be used for the preparation of a medicament for the herein disclosed treatments with the herein disclosed doses, wherein the at least one LHRH antagonist is to be administered in a dose of:
  • At least one LHRH antagonist as defined herein is provided that can be used for the preparation of a medicament for the herein disclosed treatments with the herein disclosed doses, wherein the treatment cycle is repeated after the end of the treatment-free period of the preceding treatment cycle once, twice, three-times, four-times, five-times or continuously (chronic treatment) and wherein each respective succeeding treatment cycle can be identical or different to each respective preceding treatment cycle.
  • a treatment cycle with a one-month or two-months treatment period and a two-months treatment-free period can be followed by a treatment cycle with a one-month or two-months treatment period and a five-months treatment-free period or vice versa.
  • a chronic treatment could, for instance, consist of consecutive treatment cycles with a one-month or two-months treatment period and a two-months treatment-free period or of consecutive treatment cycles with a one-month of two-months treatment period and a five-months treatment-free period or of consecutive treatment cycles with alternating one-month or two-months treatment periods and two-or five-months treatment-free periods in all possible ways.
  • testosterone castration levels of castrates and boys before reaching puberty are in the range between 0,3 to 1,2 ng/mL ("Labor und Diagnose, Herauspreparing von Lothar Thomas, 5. Erweiterte Auflage 2000, page 44, 44.2.5 Referenz Colour").
  • hormone and hormoneal within for instance the terms “hormone castration”, “chemical (hormonal) castration” or “hormone withdrawal symptoms” refer to follicle stimulating hormone (FSH), luteinizing hormone (LH) and/or testosterone.
  • FSH follicle stimulating hormone
  • LH luteinizing hormone
  • chemical (hormonal) castration is a testosterone castration and refers to a testosterone blood level of equal or below 1,2 ng/mL, preferably 0,5 ng/mL.
  • At least one LHRH antagonist as defined herein is provided that can be used for the preparation of a medicament for the herein disclosed treatments with the herein disclosed doses, wherein the chemical (hormonal) castration is a testosterone castration referring to a testosterone blood level of equal or below 1,2 ng/mL, preferably 0,5 ng/mL.
  • the at least one LHRH antagonist as defined herein is provided that can be used for the preparation of a medicament for the herein disclosed treatments with the herein disclosed doses, wherein such medicament comprises at least one additional pharmacologically active substance.
  • the at least one LHRH antagonist as defined herein is provided that can be used for the preparation of a medicament for the herein disclosed treatments with the herein disclosed doses, wherein the medicament is applied before and/or during and/or after treatment with at least one additional pharmacologically active substance.
  • the above mentioned at least one additional pharmacologically active substance includes: "smooth muscle relaxants, bladder relaxants, bladder smooth muscle relaxants, anticholinergic agents, muscarinic acetylcholine receptor antagonists, tricyclic antidepressants, Calcium antagonist, Calcium agonist, Calcium channel blockers, Calcium channel activators, Potassium antagonists, Potassium agonists, Potassium channel blockers, Potassium channel activators, alpha-adrenergic receptor antagonists, alpha-blockers, alpha-adrenoreceptor antagonists, ß3-adrenoreceptor agonists, vanilloids, vanilloid receptor antagonists, botulinum toxins" and preferably, the at least one additional pharmacologically active substance is selected of the group consisting of this agents.
  • Suitable anticholinergic agents and/or muscarinic acetylcholine receptor antagonists include oxybutynin (Benzeneacetic acid alpha-cyclohexyl-alpha-hydroxy-, 4-(diethylamino)-2-butynyl ester; synonyms: Ditropan; Ditropan XL; Oxytrol; Uromax, Chemical Abstract Services Registry Number: 5633-20-5 ), flavoxate (4H-1-Benzopyran-8-carboxylic acid 3-methyl-4-oxo-2-phenyl- 2-(1-piperidinyl)ethyl ester, Chemical Abstract Services Registry Number: 15301-69-6 ), propantheline (N-methyl-N-(1-methylethyl)-N-[2-[(9H-xanthen-9-ylcarbonyl)oxy]ethyl]-2-propanaminium, Chemical Abstract Services Registry Number: 298-50-0 ), dicyclomine ([1,1'-Bicyclohe
  • tricyclic antidepressants include imipramine (10,11-dihydro-N,N-dimethyl-5H-Dibenz[b,f]azepine-5-propanamine, synonyms: Antideprin; Berkomine; Melipramine, NSC 169866; Org 2463; Prazepine, Chemical Abstract Services Registry Number: 50-49-7 ).
  • Suitable calcium antagonists include terodiline (N-(1,1-dimethylethyl)-alpha-methyl-gamma-phenyl-benzenepropanamine, Chemical Abstract Services Registry Number: 15793-40-5 ).
  • alpha-adrenergic receptor antagonists and/or alpha-blocker and/or alpha-adrenoreceptor antagonists include terazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl]-piperazine, Chemical Abstract Services Registry Number: 63590-64-7 ), phenoxybenzamine (N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)-benzenemethanamine, synonyms: 688A; Bensylyt; Benzylyt; Dibenylin; Dibenyline; Dibenzyline; Phenoxybenzamine, Chemical Abstract Services Registry Number: 59-96-1 ), prazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)-Piperazine, synonym
  • Suitable ⁇ 3-adrenoreceptor agonists include ritobegron ([4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-2,5-dimethylphenoxy]-Acetic acid, Chemical Abstract Services Registry Number: 255734-04-4 ), YM-178, solabegron (3'-[[2-[[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-1,1'-Biphenyl]-3-carboxylic acid, Chemical Abstract Services Registry Number: 252920-94-8 ).
  • suitable vanilloids and/or vanilloid receptor antagonists include resiniferatoxin (Benzeneacetic acid, 4-hydroxy-3-methoxy-, [(2S,3aR,3bS,6aR,9aR,9bR,10R,11aR)-3a,3b,6,6a,9a,10,11,11a-octahydro-6a-hydroxy-8,10-dimethyl-11a-(1-methylethenyl)-7-oxo-2-(phenylmethyl)-7H-2,9b-epoxyazuleno[5,4-e]-1,3-benzodioxol-5-yl]methyl ester, synonyms: Daphnetoxin, Chemical Abstract Services Registry Number: 57444-62-9 ).
  • botulinum toxins examples include botulinum toxin A (BOTOX) (synonyms: AGN 191622; Allergan; Allergan (toxin); Botox; Botox Cosmetic; Botulin neurotoxin A; Botulin toxin A; Botulinium toxin type A; Botulinum neurotoxin A; Botulinum toxin type A; CBTX-A; Dysport; Linurase; NT 201; NT 201 (toxin); Nc 224; Nc 270; Neuronox; Oculinum; Reloxin; Vistabel; Xeomin, Chemical Abstract Services Registry Number: 93384-43-1 ).
  • BOTOX botulinum toxin A
  • Botox Botox Cosmetic
  • Botulin neurotoxin A Botulin toxin A
  • Botulinium toxin type A Botulinum neurotoxin A
  • Botulinum toxin type A CBTX-A
  • Dysport Lin
  • the at least one additional pharmacologically active substance is selected from the group consisting of: "smooth muscle relaxants, bladder relaxants, bladder smooth muscle relaxants, anticholinergic agents, muscarinic acetylcholine receptor antagonists, tricyclic antidepressants, Calcium antagonist, Calcium agonist, Calcium channel blockers, Calcium channel activators, Potassium antagonists, Potassium agonists, Potassium channel blockers, Potassium channel activators, alpha-adrenergic receptor antagonists, alpha-blockers, alpha-adrenoreceptor antagonists, ⁇ 3-adrenoreceptor agonists, vanilloids, vanilloid receptor antagonists, botulinum toxins".
  • the at least one additional pharmacologically active substance is selected from the group consisting of: "oxybutynin, flavoxate, propantheline, dicyclomine, tolterodine, darifenancin, solifenancin, trospium chloride, fesoterodine, imidafenacin, PSD-506, imipramine, terodiline, terazosin, phenoxybenzamine, prazosin, tamsulosin, ritobegron, YM-178, solabegron, resiniferatoxin, botulinum toxin A (BOTOX)".
  • the at least one LHRH antagonist as defined herein and, where applicable, the at least one additional pharmacologically active substance as defined herein, can be administered to various mammalian species, including human, for the herewith disclosed treatments of such mammals.
  • mammalian species are regarded as being comprised.
  • such mammals are selected from the group consisting of "human, domestic animals, cattle, livestock, pets, cow, sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat, dog, guinea pig, hamster, rat, mouse". More preferably, such mammals are human, including male human and female human. Most preferably, such mammals are male human.
  • the treatments of the present invention are surprisingly characterized in that the people treated do not show hormone withdrawal symptoms. It was surprisingly found that the applied doses of LHRH antagonists - in the course of the favorable dosage/administration schemes - are sufficiently low to prevent chemical (hormonal) castration, in particular testosterone castration, i.e. without effecting the undesired castration side effects (hormone withdrawal symptoms), while still achieving the desired therapeutic effects, such as significant improvement of nocturia and frequency of emptying in the course of the treatment of overactive bladder and/or detrusor overactivity as well as their different subforms and/or etiologies.
  • LHRH antagonists can be prepared for use according to the present invention as illustrated in the relevant prior art.
  • LHRH antagonists can be present in fast-release or slow-release (depot) formulations.
  • Slow-release (depot) formulations are preferred in order to ensure a patient-friendly treatment scheme.
  • Cetrorelix for instance, can be administered in its acetate salt form, as a reconstitute of a lyophilisate (see EP 0 611 572 for preparation and process). Alternatively and preferred, it can also be applied as a slightly soluble pamoate microparticle formulation ( WO 95/15767 ), pamoate salt ( WO 02/14347 ) or pamoate suspension ( WO 2006/069641 ), the latter being most preferred.
  • Ozarelix for instance, can be prepared and administered as disclosed in WO 00/55190 and WO 2004/030650 .
  • the at least one additional pharmacologically active substance all stereoisomers are contemplated, either in a mixture or in pure or substantially pure form.
  • the at least one additional pharmacologically active substance can have asymmetric centers at any of the carbon atoms including any one of the R radicals. Consequently, the at least one additional pharmacologically active substance can exist in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers.
  • the mixtures may have any desired mixing ratio of the stereoisomers. All these different stereochemical forms and mixtures are within the scope of the present invention.
  • the at least one additional pharmacologically active substance which has one or more centers of chirality and which occurs as racemates or as diastereomer mixtures can be fractionated by methods known per se into their optical pure isomers, i.e. enantiomers or diastereomers.
  • the separation of the at least one additional pharmacologically active substance can take place by column separation on chiral or nonchiral phases or by recrystallization from an optionally optically active solvent or with use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and subsequent elimination of the radical.
  • the at least one additional pharmacologically active substance may be present in the form of their double bond isomers as "pure” E or Z isomers, or in the form of mixtures of these double bond isomers.
  • the at least one additional pharmacologically active substance may be in the form of the tautomers.
  • the at least one additional pharmacologically active substance is in the form of any desired prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, in which cases the actually biologically active form is released only through metabolism.
  • Any compound that can be converted in vivo to provide the bioactive agent i.e. compounds of the invention is a prodrug within the scope and spirit of the invention.
  • Any biologically active compound that was converted in vivo by metabolism from any of the at least one additional pharmacologically active substance is a metabolite within the scope and spirit of the invention.
  • the at least one additional pharmacologically active substance can be administered in a known manner.
  • the route of administration may thereby be any route which effectively transports the active compound to the appropriate or desired site of action, for example orally or non-orally, in particular topically, transdermally, pulmonary, rectally, intravaginally, nasally or parenteral or by implantation. Oral administration is preferred.
  • the at least one additional pharmacologically active substances are converted into a form which can be administered and are mixed where appropriate with pharmaceutically acceptable carriers or diluents.
  • suitable excipients and carriers are described for example in Zanowiak P, Ullmann's Encyclopedia of Industrial Chemistry 2005, Pharmaceutical Dosage Forms, 1-33 ; Spiegel AJ et al., Journal of Pharmaceutical Sciences 1963, 52: 917-927 ; Czetsch-Lindenwald H, Pharm. Ind. 1961, 2: 72-74 ; Fiedler HP, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende füre 2002, Editio Cantor Verlag, p65-68 .
  • Oral administration can take place for example in solid form as tablet, capsule, gel capsule, coated tablet, granulation or powder, but also in the form of a drinkable solution.
  • the at least one additional pharmacologically active substance can for oral administration be combined with known and ordinarily used, physiologically tolerated excipients and carriers such as, for example, gum arabic, talc, starch, sugars such as, for example, mannitol, methylcellulose, lactose, gelatin, surface-active agents, magnesium stearate, cyclodextrins, aqueous or nonaqueous carriers, diluents, dispersants, emulsifiers, lubricants, preservatives and flavorings (e.g. essential oils).
  • the at least one additional pharmacologically active substance can also be dispersed in a microparticulate, e.g. nanoparticulate, composition.
  • Non-oral administration can take place for example by intravenous, subcutaneous, intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by means of implants or by ointments, creams or suppositories. Administration as sustained release form is also possible where appropriate.
  • Implants may comprise inert materials, e.g. biodegradable polymers or synthetic silicones such as, for example, silicone rubber.
  • Intravaginal administration is possible for example by means of vaginal rings.
  • Intrauterine administration is possible for example by means of diaphragms or other suitable intrauterine devices.
  • Transdermal administration is additionally provided, in particular by means of a formulation suitable for this purpose and/or suitable means such as, for example, patches.
  • the dosage may vary within a wide range depending on type and/or severity of the physiological and/or pathophysiological condition, the mode of administration, the age, gender, bodyweight and sensitivity of the subject to be treated. It is within the ability of a skilled worker to determine a "pharmacologically effective amount" of an LHRH antagonist of the invention and/or additional pharmacologically active substance. Administration can take place in a single dose or a plurality of separate dosages.
  • a suitable unit dose is, for example for the at least one additional pharmacologically active substance, from 0.001 mg to 100 mg of the active ingredient, i.e. at least one additional pharmacologically active substance, per kg of a patient's bodyweight.
  • Table 1 shows the results for nocturia, i.e. how often the study subjects got up during the night in order to urinate. The results shown are percentage variations from baseline at the beginning of the study (week 0). Table 1: Cetrorelix pamoate - Nocturia (percentage variation from baseline) Group Placebo 60+30 60+60 Week 0 0 0 0 Week 4 -17 -14 -17 Week 8 -15 -26 -26 Week 12 -23 -27 -30 Week 16 -23 -27 -25 Week 20 -24 -33 -27 Week 24 -23 -26 -29
  • Table 2 shows the results for frequency of emptying, i.e. how often the study subjects had to urinate a second time within a 2 hour test period. The results shown are percentage variations from baseline at the beginning of the study (week 0). Table 2: Cetrorelix pamoate - Frequency of emptying (percentage variation from baseline) Group Placebo 60+30 60+60 Week 0 0 0 0 Week 4 -10 -9 -16 Week 8 -8 -19 -25 Week 12 -13 -20 -24 Week 16 -13 -26 -29 Week 20 -6 -27 -25 Week 24 -5 -31 -34
  • Table 3 shows the results for the IPSS irritative subscore, i.e. the sum of the effects of nocturia, frequency of emptying and urgency to urinate. The results shown are percentage variations from baseline at the beginning of the study (week 0). Table 3: Cetrorelix pamoate - IPSS irritative subscore (nocturia, frequency of emptying, urgency to urinate) Group Placebo 60+30 60+60 Week 0 0 0 0 Week 4 -11,8 -14,8 -16,7 Week 8 -15,5 -33,3 -25 Week 12 -16,7 -29,3 -25 Week 16 -14,3 -33,3 -25 Week 20 -14,3 -33,3 -27,6 Week 24 -10 -38 -40
  • Table 4 shows the corresponding median testosterone blood levels [ng/mL] for the treatments with Cetrorelix pamoate according to above doses and administration schemes as well as for the placebo treatment.
  • Table 4 Cetrorelix pamoate - Testosterone [ng/mL] (median) Group Placebo 60+30 60+60 Week 0 4,23 3,96 3,71 Week 4 4,01 2,59 2,19 Week 8 4,30 4,01 3,70 Week 12 4,00 4,10 3,73 Week 16 4,09 3,96 n.d. Week 20 3,70 4,12 n.d. Week 24 3,67 4,30 n.d.
  • Table 5 shows the results for nocturia, i.e. how often the study subjects got up during the night in order to urinate. The results shown are mean values, how often the study subjects had to get up.
  • Table 5 Cetrorelix acetate - Nocturia (n-times, mean) Group Placebo 4x5 2x10 4x10 Week 0 2,71 2,57 2,69 2,63 Week 4 2,57 2,09 2,00 1,79 Week 8 2,49 1,94 2,06 1,78 Week 12 2,43 1,85 1,97 1,75 Week 16 2,46 1,79 1,97 1,87 Week 20 2,65 1,85 2,16 2,16
  • Table 6 shows the results for frequency of emptying, i.e. how often the study subjects had to urinate a second time within a 2 hour test period. The results shown are mean values, how often the study subjects had to urinate a second time.
  • Table 6 Cetrorelix acetate - Frequency of emptying (n-times, mean) Group Placebo 4x5 2x10 4x10 Week 0 2,40 2,49 2,29 2,86 Week 4 2,49 2,23 1,86 1,62 Week 8 2,60 2,00 1,58 1,66 Week 12 2,71 1,73 1,55 1,81 Week 16 2,80 1,52 1,45 1,65 Week 20 2,71 1,79 1,66 1,78
  • Table 7 shows the results for the IPSS irritative subscore, i.e. the sum of the effects of nocturia, frequency of emptying and urgency to urinate. The results shown are percentage variations from baseline at the beginning of the study (week 0). Table 7: Cetrorelix acetate - IPSS irritative subscore (nocturia, frequency of emptying, urgency to urinate) Group Placebo 4x5 2x10 4x10 Week 0 0 0 0 0 Week 4 -12,5 -16,7 -25 -29,3 Week 8 -14,3 -25 -33,3 -31 Week 12 0 -28,6 -33,3 -25 Week 16 0 -30,8 -42,9 -28,6 Week 20 0 -29,7 -29,2 -25
  • Table 8 shows the corresponding median testosterone blood levels [ng/mL] for the treatments with Cetrorelix acetate according to above doses and administration schemes as well as for the placebo treatment.
  • Table 8 Cetrorelix acetate - Testosterone [ng/mL] (median) Group Placebo 4x5 2x10 4x10 Week 0 3,93 3,42 3,27 3,41 Week 4 3,18 2,95 4,41 2,17 Week 8 3,39 3,77 3,73 3,82 Week 12 3,06 4,11 4,45 4,32 Week 16 3,77 3,91 4,16 4,32 Week 20 4,02 3,49 4,12 4,06
  • Table 9 shows the results for nocturia, i.e. how often the study subjects got up during the night in order to urinate. The results shown are mean values, how often the study subjects had to get up.
  • Table 9 Ozarelix - Nocturia (n-times, mean) Group Placebo 15+15 Week 0 2,92 2,73 Week 4 2,33 1,83 Week 8 2,04 1,43 Week 12 2,17 1,54 Week 16 2,17 1,54 Week 20 2,26 1,50 Week 24 2,23 1,54
  • Table 10 shows the results for frequency of emptying, i.e. how often the study subjects had to urinate a second time within a 2 hour test period. The results shown are mean values, how often the study subjects had to urinate a second time.
  • Table 10 Ozarelix - Frequency of emptying (n-times, mean) Group Placebo 15+15 Week 0 2,75 2,90 Week 4 2,46 2,48 Week 8 2,00 2,11 Week 12 2,09 1,82 Week 16 2,04 1,75 Week 20 2,00 1,71 Week 24 2,05 1,75
  • Table 11 shows the results for urgency to urinate, i.e. how often the study subjects had difficulties to delay the urination. The results shown are mean values, how often the study subjects had difficulties.
  • Table 11 Ozarelix - Urgency to urinate (n-times, mean) Group Placebo 15+15 Week 0 2,92 2,80 Week 4 2,04 2,17 Week 8 2,13 1,89 Week 12 2,22 1,75 Week 16 2,13 1,39 Week 20 2,26 1,71 Week 24 2,09 1,89
  • Table 12 shows the corresponding median testosterone blood levels [ng/mL] for the treatments with Ozarelix according to above doses and administration schemes as well as for the placebo treatment.
  • Table 12 Ozarelix - Testosterone [ng/mL] (median) Group Placebo 15+15 Week 0 3,95 3,57 Week 4 4,16 2,97 Week 8 3,99 4,19 Week 12 3,98 4,11 Week 16 4,00 3,82 Week 20 3,50 3,92 Week 24 4,22 3,86

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EP07103483A EP1967202A1 (fr) 2007-03-05 2007-03-05 Utilisation d'antagonistes LHTH pour le traitement des symptômes de tractus urinaires faibles, en particulier la vessie hyperactive et/ou hyperactivité du détrusor
US12/042,522 US20090075937A1 (en) 2007-03-05 2008-03-05 Lhrh antagonists for the treatment of lower urinary tract symptoms
CN200880007201A CN101657211A (zh) 2007-03-05 2008-03-05 Lhrh拮抗剂在治疗下泌尿道症状，特别是膀胱活动过度和/或逼肌活动过度中的应用
PCT/EP2008/052640 WO2008107446A1 (fr) 2007-03-05 2008-03-05 Utilisation d'antagonistes de lhrh pour traitement de symptômes du tractus urinaire inférieur, vessie hyperactive et/ou hyperactivité du détrusor en particulier
EP08709284A EP2131854A1 (fr) 2007-03-05 2008-03-05 Utilisation d'antagonistes de lhrh pour traitement de symptômes du tractus urinaire inférieur, vessie hyperactive et/ou hyperactivité du détrusor en particulier
MX2009009320A MX2009009320A (es) 2007-03-05 2008-03-05 Uso de antagonistas de lhrh para el tratamiento de sintomas del tracto urinario inferior, en particular vejiga hiperactiva y/o hiperactividad detrusora.
KR1020097018620A KR20100014923A (ko) 2007-03-05 2008-03-05 하부 요로 증상, 특히 과민성 방광 및/또는 배뇨근 과활동성을 치료하기 위한 ｌｈｒｈ 길항제의 용도
AU2008223841A AU2008223841A1 (en) 2007-03-05 2008-03-05 Use of LHRH antagonists for the treatment of lower urinary tract symptoms, in particular overactive bladder and/or detrusor overactivity
BRPI0808488-2A BRPI0808488A2 (pt) 2007-03-05 2008-03-05 Uso de antagonistas de lhrh para o tratamento de sintomas do trato urinário inferior, em particular bexiga superativa e/ou superatividade do detrusor
JP2009552194A JP2010520257A (ja) 2007-03-05 2008-03-05 下部尿路症状、特に過活動膀胱及び／又は排尿筋過活動の治療のためのｌｈｒｈアンタゴニスト類の使用
CA002679690A CA2679690A1 (fr) 2007-03-05 2008-03-05 Utilisation d'antagonistes de lhrh pour traitement de symptomes du tractus urinaire inferieur, vessie hyperactive et/ou hyperactivite du detrusor en particulier
RU2009136642/15A RU2009136642A (ru) 2007-03-05 2008-03-05 Антагонисты рилизинг-фактора лютеинизирующего гормона (лг-рг) в качестве средства при приготовлении лекарства для лечения или профилактики симптомов расстройств нижних мочевых путей
ZA200905306A ZA200905306B (en) 2007-03-05 2009-07-30 Use of LHRH antagonists for the treatment of lower urinary tract symptoms, in particular overactive bladder and/or detrusor overactivity
IL200182A IL200182A0 (en) 2007-03-05 2009-07-30 Use of lhrh antagonists for the treatment of lower urinary tract symptoms, in particular overactive bladder and/or detrusor overactivity

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ZA200905306B (en) 2010-04-28
EP2131854A1 (fr) 2009-12-16
JP2010520257A (ja) 2010-06-10
WO2008107446A1 (fr) 2008-09-12
MX2009009320A (es) 2009-09-10
US20090075937A1 (en) 2009-03-19
CN101657211A (zh) 2010-02-24
AU2008223841A1 (en) 2008-09-12
KR20100014923A (ko) 2010-02-11
CA2679690A1 (fr) 2008-09-12
IL200182A0 (en) 2010-04-15
BRPI0808488A2 (pt) 2014-07-15
RU2009136642A (ru) 2011-04-10

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